Ethical, legal and social aspects of human cerebral organoids and their governance in Germany, the United Kingdom and the United States.

Human cerebral organoids (HCOs) are model systems that enable researchers to investigate the human brain in ways that had previously been impossible. The emergence of HCOs was accompanied by both expert and layperson discussions concerning the possibility of these novel entities developing sentience or consciousness. Such concerns are reflected in deliberations about how to handle and regulate their use. This perspective article resulted from an international and interdisciplinary research retreat "Ethical, Legal and Social Aspects of Human Cerebral Organoids and their Governance in Germany, the United Kingdom and the United States", which took place in Tübingen, Germany, in August 2022. The retreat focused on whether HCO research requires new ethical and regulatory approaches. It addressed epistemic issues around the detection and theorisation of consciousness, ethical concerns around moral status and research conduct, difficulties for legislation and guidelines managing these entities, and public engagement.

In vitro modeling of the neurobiological effects of glucocorticoids: A review.

Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the adrenal glands as a result of HPA-axis activation. The release of GCs is implicated with several neurobiological changes that are associated with negative consequences of chronic stress and the onset and course of psychiatric disorders. Investigating the underlying neurobiological effects of GCs may help to better understand the pathophysiology of stress-related psychiatric disorders. GCs impact a plethora of neuronal processes at the genetic, epigenetic, cellular, and molecular levels. Given the scarcity and difficulty in accessing human brain samples, 2D and 3D in vitro neuronal cultures are becoming increasingly useful in studying GC effects. In this review, we provide an overview of in vitro studies investigating the effects of GCs on key neuronal processes such as proliferation and survival of progenitor cells, neurogenesis, synaptic plasticity, neuronal activity, inflammation, genetic vulnerability, and epigenetic alterations. Finally, we discuss the challenges in the field and offer suggestions for improving the use of in vitro models to investigate GC effects.

Ethical Implications in Making Use of Human Cerebral Organoids for Investigating Stress-Related Mechanisms and Disorders.

The generation of three-dimensional cerebral organoids from human-induced pluripotent stem cells (hPSC) has facilitated the investigation of mechanisms underlying several neuropsychiatric disorders, including stress-related disorders, namely major depressive disorder and post-traumatic stress disorder. Generating hPSC-derived neurons, cerebral organoids, and even assembloids (or multi-organoid complexes) can facilitate research into biomarkers for stress susceptibility or resilience and may even bring about advances in personalized medicine and biomarker research for stress-related psychiatric disorders. Nevertheless, cerebral organoid research does not come without its own set of ethical considerations. With increased complexity and resemblance to in vivo conditions, discussions of increased moral status for these models are ongoing, including questions about sentience, consciousness, moral status, donor protection, and chimeras. There are, however, unique ethical considerations that arise and are worth looking into in the context of research into stress and stress-related disorders using cerebral organoids. This paper provides stress research-specific ethical considerations in the context of cerebral organoid generation and use for research purposes. The use of stress research as a case study here can help inform other practices of in vitro studies using brain models with high ethical considerations.

In vitro modeling of glucocorticoid mechanisms in stress-related mental disorders: Current challenges and future perspectives.

In the last decade, in vitro models has been attracting a great deal of attention for the investigation of a number of mechanisms underlying neurological and mental disorders, including stress-related disorders, for which human brain material has rarely been available. Neuronal cultures have been extensively used to investigate the neurobiological effects of stress hormones, in particular glucocorticoids. Despite great advancements in this area, several challenges and limitations of studies attempting to model and investigate stress-related mechanisms in vitro exist. Such experiments often come along with non-standardized definitions stress paradigms in vitro, variations in cell models and cell types investigated, protocols with differing glucocorticoid concentrations and exposure times, and variability in the assessment of glucocorticoid-induced phenotypes, among others. Hence, drawing consensus conclusions from in-vitro stress studies is challenging. Addressing these limitations and aligning methodological aspects will be the first step towards an improved and standardized way of conducting in vitro studies into stress-related disorders, and is indispensable to reach the full potential of in vitro neuronal models. Here, we consider the most important challenges that need to be overcome and provide initial guidelines to achieve improved use of in vitro neuronal models for investigating mechanisms underlying the development of stress-related mental disorders.

Dual-specificity phosphatases in mental and neurological disorders.

The dual-specificity phosphatase (DUSP) family includes a heterogeneous group of protein phosphatases that dephosphorylate both phospho-tyrosine and phospho-serine/phospho-threonine residues within a single substrate. These protein phosphatases have many substrates and modulate diverse neural functions, such as neurogenesis, differentiation, and apoptosis. DUSP genes have furthermore been associated with mental disorders such as depression and neurological disorders such as Alzheimer's disease. Herein, we review the current literature on the DUSP family of genes concerning mental and neurological disorders. This review i) outlines the structure and general functions of DUSP genes, and ii) overviews the literature on DUSP genes concerning mental and neurological disorders, including model systems, while furthermore providing perspectives for future research.

Methodologies of Neuroepigenetic Research: Background, Challenges and Future Perspectives.

Over the last years, interest in epigenetic mechanisms has strongly increased in the field of neuroscience. Neuroepigenetics has intensely evolved and now refers to the assessment of a variety of epigenetic marks which can be found across several regions of the healthy or diseased brain. These marks include DNA (hydroxy)methylation, a large diversity of post-translational histone modifications and an increasing number of non-coding RNAs. The present chapter aims to concisely summarize the techniques used to study these mechanisms in the brain and provides an overview of their current challenges along with future perspectives that will allow the field to move forward.

From Epigenetic Associations to Biological and Psychosocial Explanations in Mental Health.

The development of mental disorders constitutes a complex phenomenon driven by unique social, psychological and biological factors such as genetics and epigenetics, throughout an individual's life course. Both environmental and genetic factors have an impact on mental health phenotypes and act simultaneously to induce changes in brain and behavior. Here, we describe and critically evaluate the current literature on gene-environment interactions and epigenetics on mental health by highlighting recent human and animal studies. We furthermore review some of the main ethical and social implications concerning gene-environment interactions and epigenetics and provide explanations and suggestions on how to move from statistical and epigenetic associations to biological and psychological explanations within a multi-disciplinary and integrative approach of understanding mental health.